基因编辑技术CRISPR/Cas9专利的认定

基因编辑技术CRISPR/Cas9自出现以来吸引了广泛关注。两个研究团队对此项技术在美国专利归属的争夺引起了关于此项技术是否可专利以及其专利归属的讨论。现通过分析美国的专利制度论证基因编辑技术CRISPR/Cas9的可专利性,并通过介绍美国专利制度中确定专利权人基本原则的转变,探求基因编辑技术CRISPR/Cas9专利的归属问题。最后,通过现有资料和专利制度的相关知识预测专利的最终归属,以及对如何应对基因编辑技术CRISPR/Cas9在我国的专利申请作出判断。     

牛雄性特异性DNA序列获美国专利并在美国探讨其商业化

日本伊藤火腿公司宣布,可用作牛受精卵性别鉴定的雄牛特异性DNA序列于1995年10月24日获得美国专利。美国专利是继澳大利亚、新西兰之后的第3个。作为牛受精卵雌雄性鉴别盒“XY选择器”日本火腿公司已开始在日本销售这种雄性特异DNA序列。获得美国专利后该成果将作为试剂盒在美国尝试商业化。     

加强对基因专利的研究

基因专利是生物技术产业知识产权保护的最主要形式,被认为是生物技术产业发展的金钥匙。谁握有基因专利,谁就将占有生物技术产业发展的空间、占有未来的财富。近几年,随着人类基因组、基因功能研究的迅速进展,极大地激发了投资者的想象空间和对获取基因专利的高涨热情。前几年曾出现了以跑马圈地的方式申报基因专利的高潮,我国也曾有过一次申请上百条基因专利的例子。目前,在美国已授权了2万余个基因或基因相关分子的专利.     

藻类性状转化技术获得专利

《日经生物技术》2000年4月24日号第16页报道：美国Martek Biosciences公司(马里兰州Columbia)和美国Carnegie Institute of Washington研究所4月11日宣布,覆盖了真核藻类性状转化的方法获得了美国专利,专利号为6027900。 如果使用这项专利,就可迅速提高从多种藻类基因中鉴定出有使用价值基因的能力。美国Martek公司拥有将这项技术用于商业开发的所有权利。 得到认可的在特定藻类中导入DNA的这项专利技术是Carnegie研究所植物生物学部门Kirk Apt和Arthur Grossman以及Martek公司共同开发的。Martek公司还提供了一部分研究资金。 在动物及植物细胞中表达外来基因而使用的启动子对藻类没有启动功能。研究人员研究藻类基因高效表达时发现在藻类光合作用的基因启动子区域可诱导来自其他生物的基因表达。 这项专利还涵盖了简单地鉴定和分离引起性状转化的藻类细胞标记的使用。Martek公司获得了含有新发现启动子的所有载体及用该载体进行性状转化的所有细胞的商品化权利。该公司会长兼最高经营负责人Henry Linsert说：“我公司因此可确立在藻类生物技术商品化方面的主导地位。使用新一技术就能从藻类染色体中搜索到农作物育种用的性状。用藻类细胞可生产有价值的植物蛋白和动物蛋白”。该公司现在的兴趣已转向用藻类鉴定参与胡萝卜素、维生素E、类固醇、异黄酮、长链多不饱和脂肪酸等生物合成的基因。 因为藻类与高等植物的基因结构和生物化学途径类似,所以科学家最大的希望是将藻类作为新的基因供给源。孙国凤     

基因定位新技术

最近,美国加州伯克利劳伦斯(LBL)实验室的科学家,创立了一种新的染色体基因定位法。研究者将该项新技术称为“随机-断裂定位法”。声称对标定染色体端部以里的DNA序列快速方便。该研究室细胞分子生物学组的Game博士认为,这项技术在只知DNA序列所在染色体情况下尤为有用。虽只适用于重复序列较少的DNA序列,但应能包括需进行定位的多数基因。染色体断裂设想只发生一次断裂的染色体,可帮助理解随机-断裂定位法。因为一个发生一次断裂的染色体,包含     

基于专利分析的肿瘤基因PCR诊断技术研究

肿瘤目前成为人类健康和生命的重要危胁,肿瘤基因诊断是对肿瘤的各种原癌基因、抑癌基因进行检测,聚合酶链反应(polymerase chain reaction,PCR)技术是目前临床基因诊断应用最广泛的诊断技术,具有普及率高、特异性好、简便快捷等特点。肿瘤基因PCR诊断技术可以用于已知基因突变的检测,快速了解突变状态,有效制定治疗方案,为肿瘤患者带来福音。本研究主要基于专利数据,对肿瘤基因PCR诊断技术进行分析,探讨了全球与中国在肿瘤基因PCR诊断技术领域的发展现状与趋势。在Innography数据库共检索到PCR技术相关专利16,939件,专利家族6,285件。在肿瘤基因PCR诊断技术领域中,荧光定量PCR技术占比较大,约占肿瘤基因PCR诊断技术总量的三分之一。从技术技术生命周期来看,肿瘤基因PCR诊断技术目前仍处在高速发展阶段。美国是肿瘤基因PCR诊断技术的发展领先国家。该技术的主要来源国为美国,全球42.09%的专利来自美国,同时美国也是同族专利的主要分布地区。在肿瘤基因PCR诊断技术领域,排名前15位的顶尖机构中,来自美国的机构有7所。中国在肿瘤基因PCR诊断技术领域起步较晚,但发展迅速,在该技术领域申请的专利数量仅次于美国。中国申请的肿瘤基因PCR诊断技术的专利绝大多数都只在中国进行专利保护,并没有布局全球市场的意愿。     

mtDNA基因树拓扑距离比较和基因分群

基因树间拓扑距离数据的比较进一步证明：与分割拓扑距离相比,能经拓扑距离是一种更为精确的测度,利用相对通经拓扑距离构建了8个基因的拓扑距离树。基因的拓扑距离树能直观地反映不同基因树的拓扑结构差异大小,可用来对基因进行分群。此外,发现不同DNA序列用于构建多基因树中其系统发生信息存在“累加”,“合取”,“含盖”,“相斥”等数学关系。这可解释在mtDNA基因组中一些基因比另一些基因更适合用来的构建树的结果。结果提示从GenBank中应选择具有累加基因的DNA序列或蛋白质氨基酸序列合并来构建物种。在讨论中还提出了一种获得真树的新建树策略。     

抗真菌病重组植物获得美国专利

美国DNA Plant Technology公司1990年7月就抗真菌病重组植物获得美国专利,专利号为US4751081.这项专利的内容是壳质酶,它能分解真菌的细胞壁,从而摧毁真菌.这种酶的基因是经基因操作整合入植物基因组中.从而提高重组植物的抗病力.用壳质酶切断的壳质分解产物是引发物质,刺激植物的免疫体系,增加对真菌病的抵抗力.因此该公司期望除在栽培期间显示耐病性外,还能防止在收获后保存时引起的真菌污染.现     

蝎毒液肽基因内含子剪接信号分析

从中国蝎Buthus martensii Karsch基因组DNA中分离到两个毒液基因的内含子。在此基础上,通过编辑和分析目前已出版的蝎毒液肽基因内含子序列,确定了这类基因内含子剪接信号的共有序列,并将其与其它其它物种进行了比较。本文的结果对于研究蝎毒液肽前体mRNA的剪接机制以及比较不同物种之间内含子进化和功能的关系具有参考价值。     

FLAVR SAVR基因已获欧洲专利

Calgene公司已获得多聚半乳糖醛酸酶(PG)基因亦称FLAVR SAVR基因的欧洲专利(NO.240208B)。事实上,该公司在1989年就已获得FLAVR SAVR基因在美国的专利。1994年,公司宣布,它已与Zenea AVP和Campbell Soup Company达成协议,授予Calgeae公司独家在全世界的专利,利用FLAVR SAVR基因研制新鲜番茄的市场。 Calgene公司总裁兼首席执行官Roger Salqulst声称,FLAVR SAVR基因是延迟蔓上成熟的新鲜番茄软化方法中唯一经证明并许可的方法。因推迟番茄软化是将味道确实鲜美的番茄通过美国超级市场传     

Patentable subject matter: morally neutral and context free

AMP v. USPTO otherwise known as the ACLU/Myriad "gene patenting" case has famously pitted the American Civil Liberties Union (ACLU) against Myriad Genetics. DNA patent litigation is not novel, but this case is distinct from typical cases involving commercial rivals; heretofore neither side has an interest in the commercially suicidal attacking of the underlying concept of DNA patents. The ACLU, representing the plaintiffs, has no such qualms. And the ACLU is fighting dirty: the United States patent system is effectively moral and social-context neutral, but the ACLU has succeeded in making social and political concerns the highlight of their legal case, even reframing DNA as per our human understanding, as information, and as distinct from a simple double helical macromolecule. The relevance of the case exceeds the bounds of DNA patents, as reflected in the number of amicus briefs filed, and threatens many other industries, particularly those that rely on extracted biomaterials.     

Gene patents and capital investment

Will the US Supreme Court''s ruling that genes can no longer be patented in the USA boost venture capital investment into biotech and medical startup companies?Three years ago, Noubar Afeyan, managing partner and CEO of Flagship Ventures, an early-stage venture capital firm in Cambridge, Massachusetts, USA, was working with a biotech start-up company developing techniques for BRCA gene testing for breast cancer risk that avoided the patents held by Myriad Genetics, a molecular diagnostics company in Salt Lake City (Utah, USA) and the only operator in the field. However, despite the promise of the start-up''s techniques, investors were put off by Myriad''s extensive patent portfolio and fiercely defensive tactics: “A lot of investors were simply not willing to take that chance, even though our technology was superior in many ways and patentably different,” Afeyan said. The effort to launch the start-up ultimately failed.…it is also not clear how the Supreme Court''s ruling will affect the […] industry at large, now that one of the most contested patents for a human gene has been ruled invalidAfeyan believes the prospects for such start-ups improved on the morning of 13 June 2013 when the US Supreme Court ruled in an unanimous vote that Myriad''s fundamental patents on the BRCA1 and BRCA2 genes themselves are invalid, opening up the field to new competitors. The court''s ruling, however, validated Myriad''s patents for BRCA cDNA and methods-of-use.The court''s decision comes at a time when venture capital investment into the life sciences is projected to decline in the years ahead. Some believe that the court''s decision sets a precedent and could provide a boost for products, diagnostics and other tests under development that would have been legally difficult in the light of existing patents on human and other DNA sequences.The US Patent Office issued the original patents for the BRCA 1 and BRCA2 genes in 1997 and 1998 for the US National Institute of Environmental Health Services, the University of Utah and Myriad Genetics. One year earlier, Myriad had launched its first diagnostic test for breast cancer risk based on the two genes and has since aggressively defended it against both private and public competitors in court. Many universities and hospitals were originally offering the test for a lower cost, but Myriad forced them to stop and eventually monopolized BRCA-based diagnostics for breast cancer risk in the USA and several other countries.“Myriad did not create anything,” Justice Clarence Thomas wrote in the Supreme Court''s decision. “To be sure, it found an important and useful gene, but separating that gene from its surrounding genetic material is not an act of invention.” Even so, the court did uphold Myriad''s patents on the methodology of its test. Ron Rogers, a spokesman for the biotech firm, said the Supreme Court had “affirmed the patent eligibility of synthetic DNA and underscored the importance and applicability of method-of-use patents for gene-based diagnostic tests. Before the Supreme Court case we had 24 patents and 520 claims. After the Supreme Court decision, we still have 24 patents. […] [T]he number of our patent claims was reduced to 515. In the Supreme Court case itself, only nine of our 520 patent claims were at issue. Of the nine, the Supreme Court ruled that five were not patent-eligible and they ruled that four were patent-eligible. We still have strong intellectual property protection surrounding our BRCA test and the Supreme Court''s decision doesn''t change that.”Within hours of the ruling, capitalism kicked into high gear. Two companies, Ambry Genetics in Alieso Viejo, California, and Gene by Gene Ltd in Houston, Texas, USA, announced that they were launching tests for the BRCA1 and BRCA2 genes for less than the US$3,100 Myriad has been charging privately insured patients and US$2,795 for patients covered by Medicare—the government health plan for the elderly and disabled. Several other companies and universities also announced they would be offering BRCA testing.Entrepreneur Bennett Greenspan, a managing partner of Gene by Gene, explained that his company had been poised to offer BRCA testing if the Supreme Court ruled against Myriad. He said, “We had written a press release with our PR firm a month before the release of the Supreme Court with the intention that if the Supreme Court overruled the patent or invalidated the patent that we would launch right away and if they didn''t, we would just tear up the press release.” His company had previously offered BRCA gene testing in Israel based on guidelines from the European Union.Myriad Genetics has not given up defending its patents, however. On 9 and 10 July 2013, it slapped Ambry and Gene by Gene with lawsuits in the US District Court in Salt Lake City for allegedly infringing on patents covering synthetic DNA and methods-of-use related to the BRCA1 and BRCA2 genes. Rogers commented that the testing processes used by the firms “infringes 10 patents covering synthetic primers, probes and arrays, as well as methods of testing, related to the BRCA1 and BRCA2 genes.”On 6 August 2013, Ambry countersued Myriad, arguing that the company “continues a practice of using overreaching practices to wrongfully monopolize the diagnostic testing of humans'' BRCA1 and BRCA2 genes in the United States and to attempt to injure any competitor […] Due to Myriad''s anticompetitive conduct, customers must pay significantly higher prices for Myriad''s products in the relevant market, often nearly twice as high as the price of Ambry''s products and those of other competitors” [1].Just as the courts will have to clarify whether the competitors in this case infringe on Myriad''s patents, it is also not clear how the Supreme Court''s ruling will affect the biotech and diagnostics industry at large, now that one of the most contested patents for a human gene has been ruled invalid. In recent years, venture capital investment into the life sciences has been in decline. The National Venture Capital Association and the Medical Innovation & Competitiveness Coalition reported from a survey that, “An estimated funding loss of half a billion dollars over the next three years will cost America jobs at a time when we desperately need employment growth” [2]. The survey of 156 venture capital firms found that 39% of respondents said they had reduced investment in the life sciences during the previous three years, and the same proportion intended to do so in the next three years. “[US Food and Drug Administration] FDA regulatory challenges were identified as having the highest impact on these investment decisions,” the report states, adding that many investors intended to shift their focus from the US towards Europe and the Asia/Pacific region.Another report from the same groups explains how public policy involving the FDA and other players in “the medical innovation ecosystem”—including the US patent system, public agencies, tax policy, securities regulation, immigration laws and private groups such as insurers—affect the decisions of investors to commit to funding medical innovation [3].Some investors think that the court decision about the patentability of human DNA will increase confidence and help to attract investors back to the life sciencesSome investors think that the court decision about the patentability of human DNA will increase confidence and help to attract investors back to the life sciences. “The clarity is helpful because for the longest time people didn''t do things because of ambiguity about whether those patents would be enforceable,” Afeyan said. “It''s one thing to not do something because of a patent, it''s another to not do something because you know that they have patents but you''re not sure what it''s going to stop you from doing because it hasn''t been really fully fleshed out. Now I think it is reasonably well fleshed out and I think you will see more innovation in the space.”Others also appreciate the clarification from the Supreme Court about what is a patentable invention in regard to human genes and DNA. “The Myriad decision was a very solid reading of the underlying purpose of our patent law, which is to reward novel invention,” commented Patrick Chung, a partner with New Enterprise Associates, a venture capital firm in Menlo Park, California, which invested in 23andMe, a personal genomics company based in Mountain View (California, USA), and who serves on the 23andMe board.But not everyone agrees that the Supreme Court''s decision has provided clarity. “You could spin it and say that it was beneficial to create some certainty, but at the end of the day, what the Court did was reduce the scope of what you''re allowed to get patent claims on,” said Michael Schuster, a patent lawyer and Intellectual Property Partner and Co-Chair of the Life Sciences Group at Fenwick & West LLP in San Francisco, California, USA. “It''s going to be a continuing dance between companies, smart patent lawyers, and the courts to try to minimize the impact of this decision.”Kevin Noonan, a molecular biologist and patent lawyer with McDonnell Boehnen Hulbert & Berghoff LLP in Chicago, Illinois, USA, commented that he does not expect the Supreme Court decision will have much of an impact on venture investments or anything else. “This case comes at a time fortunately when biotechnology is mature enough so that the more pernicious effects of the decision are not going to be quite as harmful as they would if this had happened ten, 15 or 20 years ago,” he said. “We''re now in the ‘post-genomic'' era; since the late ‘90s and turn of the century, the genomic and genetic data from the Human Genome Project have been on publicly available databases. As a consequence, if a company didn''t apply for a patent before the gene was disclosed publicly, it certainly is not able to apply for a patent now. The days of obtaining these sequences and trying to patent them are behind us.”Noonan also noted that the Myriad Genetics patents were due to expire in 2014–2015 anyway. “Patents are meaningless if you can''t enforce them. And when they expire, you can no longer enforce them. So it really isn''t an impediment to genetic testing now,” he explained. “What the case illustrates is a disconnect between scientists and lawyers. That''s an old battle.”George Church, professor of genetics at Harvard Medical School (Boston, Massachusetts, USA) and Director of the Personal Genome Project, maintains that the Supreme Court decision will have minimal influence on the involvement of venture capitalists in biotech. “I think it''s a non-issue. It''s basically addressing something that was already dead. That particular method of patenting or trying to patent components of nature without modification was never really a viable strategy and in a particular case of genes, most of the patents in the realm of bio-technology have added value to genes and that''s what they depend on to protect their patent portfolio—not the concept of the gene itself,” he said. “I don''t know of any investor who is freaked out by this at all. Presumably there are some, because the stock oscillates. But you can get stock to oscillate with all kinds of nonsense. But I think the sober, long-term investors who create companies that keep innovating are not impacted.”Church suggests that the biggest concern for Myriad now is whole-gene sequencing, rather than the Supreme Court''s decision. “Myriad should be worrying about the new technology, and I''m sure they''ve already considered this. The new technology allows you to sequence hundreds of genes or the whole genome for basically the price they''ve been charging all along for two genes. And from what I understand, they are expanding their collection to many genes, taking advantage of next generation sequencing as other companies have already,” he said.Whatever its consequences in the US, the Supreme Court''s decision will have little impact on other parts of the world, notably Europe, where Myriad also holds patents on the BRCA genes in several countries. Gert Matthijs, Head of the Laboratory for Molecular Diagnostics at the Centre for Human Genetics in Leuven, Belgium, says that even though the US Supreme Court has invalidated the principle of patenting genes in America, the concept remains in Europe and is supported by the European Parliament and the European Patent Convention. “Legally, nothing has changed in Europe,” he commented. “But there is some authority from the US Supreme Court even if it''s not legal authority in Europe. Much of what has been used as arguments in the Supreme Court discussions has been written down by the genetics community in Europe back in 2008 in the recommendations on behalf of the European Society for Human Genetics. The Supreme Court decision is something that most of us in Europe would agree upon only because people have been pushing towards protecting the biotech industry that the pendulum was so way out in Europe.”Benjamin Jackson, Senior Director of legal affairs at Myriad Genetics, commented that Myriad holds several patents in Europe that are not likely to be affected by the Supreme Court''s ruling. “The patent situation both generally and for Myriad is a lot clearer in Europe. The European Union Biotech Directive very clearly says that isolated DNA is patentable even if it shares the same sequence as natural DNA,” he said. “Right now, it''s pretty uncontroversial, or at least it''s well settled law basically in Europe that isolated DNA is patentable.” However, while the Directive states that “biological material which is isolated from its natural environment or produced by means of a technical process” might be patentable “even if it previously occurred in nature”, the European Patent Office (EPO) in Munich, Germany, requires that the subject matter is an inventive step and not just an obvious development of existing technology and that the industrial application and usefulness must be disclosed in the application.Myriad has opened a headquarters in Zurich and a lab in Munich during the past year, hoping to make inroads in Europe. In some EU countries, Myriad offers its BRCA test as part of cancer diagnosis. In other countries, BRCA testing is conducted at a fraction of what Myriad charges in the USA, either because institutions ignore the patents that are not enforced in their jurisdictions, or because these countries, such as Belgium, were not included in the patent granted by the European Patent Office. Moreover, in various countries BRCA testing is only available through the healthcare system and only as part of a more extensive diagnosis of cancer risk. In addition, as Matthijs commented, “[t]he healthcare system in Europe is very heterogeneous and that''s also of course a big impediment for a big laboratory to try and conquer Europe because you have to go through different reimbursement policies in different countries and that''s not easy.”Ultimately, it seems the Supreme Court''s decision might turn out to have little impact on biotech firms in either the USA or Europe. Technological advances, in particular new sequencing technologies, might render the issue of patenting individual genes increasingly irrelevant.     

Opposition to Myriad Genetics patents and their total or partial revocation in Europe: early conclusions

The proceedings instituted against three European patents held by the US company Myriad Genetics, on the BRCA1 gene and the breast cancer diagnosis gene, resulted in the total or partial revocation of these patents. These decisions put an end to the legal monopoly claimed by Myriad Genetics on the BRCA1 gene and on breast cancer gene tests, and left the field open to European geneticists to develop and implement their test methods within the framework of a clinical not-for-profit organization. The opposition procedure, through which any actor is allowed to challenge European patents, was used by geneticists doctors in Europe to refuse the emergence of an industrial monopoly on a medical service offered in a clinical context. The decision to revoke or strongly limit these patents was based on the European Patent Office's refusal to establish an invention priority on a sequence that had errors at the time the application was filed by the patent holder, in September 1994. The patent holder was granted an invention priority only on 24 March 1995, when it filed an application for a corrected sequence of the gene. But by then the BRCA1 gene sequence had already been divulged in a public data base, Genbank, from October 1994, notably by Myriad. Myriad Genetics' patents were thus victims of the patent race that prompted the firm to file multiple patent applications on insufficiently validated sequences, and of the conflict between diffusion in the public domain and the novelty requirement. Opposition to the patents, undertaken by a coalition of medical institutions, human genetic societies, two States, Holland and Austria, an environmental protection organization (Greenpeace), and the Swiss Labour Party, made it possible to preserve and develop the clinical economy of genetic tests in Europe. It resulted in amendments to intellectual property laws in France and thus extended the possibility of using compulsory licences for public health purposes to in vitro diagnosis.     

专利微生物菌种的保藏与发放统计分析

对WIPO公开的"国际保藏机构2001～2010年专利微生物保藏与发放"数据进行了统计分析。结果表明:全世界的专利菌种保藏量与发放量处于快速增长中;美国是专利菌种保藏与发放量最多的国家;近年中国的专利菌种年保藏量实现三连冠,但专利菌种的发放率处于极低水平。     

生物学发明及其专利保护

本参考中国专利法,欧洲专利法及美国、日本的相关专利法条和有关国际公约讨论了生物学发明及其获得专利保护的一般方法和原则,以期帮助有关企业和科研机构能有效地对相应地发明进行专利保护。     

中国专利基因数据库的创建

创建了中国专利基因数据库NASDAP(http://nasdap.generank.org/).整合了专利序列、专利微阵列、专利基序和专利单核苷酸多态性(singlenucleotidepolymorphism,SNP)等专利对象,并实现对上述对象的BLAST检索或基序扫描服务.这为相关研究的立项、基因研发状态追踪以及基因专利申请和审批等工作提供了生物信息平台,并可为药物开发、疾病诊断和农业等生命科学相关研究的思路启发及知识产权战略制定等方面工作提供参考.     

Gene patents in the US - focusing on what really matters

ABSTRACT: With new technologies, concerns about gene patent claims regarding isolated DNA are becoming less relevant, but broad method claims could be more problematic.     

在我国失效的美国心血管疾病治疗药物的PCT 专利申请数据挖掘

目的：从没有在中国得到保护的美国专利申请或专利中寻找心血管疾病治疗药物研发的思路。方法：对申请日从2005 年1 月1 日至2014 年12 月31 日的美国心血管系统疾病治疗药物PCT 申请进入中国国家阶段后失效的专利申请及专利数据进行整序和分析,依据其在美国本土的法律状态确定其技术含金量。结果：未得到中国专利保护的美国心血管系统疾病治疗药物PCT 申请共174 件,其中170 件申请了美国优先权或进入了美国国家阶段。结论：170 件美国心血管系统疾病治疗药物PCT 申请在美国申请优先权,大多数因美国的优先权临时申请过期而放弃。14 件在美国本土的优先权申请失效,其所含信息量应该相当于公开发表的论文的信息量,23 件在美国本土优先权授权的专利技术具有一定的技术含金量,目前在中国已经进入公知公用领域,经过市场价值评估后可以无偿使用。